The present invention relates to new polypeptide compound and a salt thereof which are useful as a medicament.
In U.S. Pat. No. 5,376,634, there are disclosed the polypeptide compound and a pharmaceutically acceptable salt thereof, which have antimicrobial activities (especially antifungal activity).
The present invention relates to new polypeptide compound and a salt thereof.
More particularly, it relates to new polypeptide compound and a salt thereof, which have antimicrobial activities [especially, antifungal activities, in which the fungi may include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium and the like.], inhibitory activity on xcex2-1,3-glucan synthase, and further which are expected to be useful for the prophylactic and/or therapeutic treatment of Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the prophylactic and/or therapeutic treatment of infectious diseases including Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal.
The object polypeptide compound of the present invention are new and can be represented by the following general formula [I] (SEQ ID No: 1): 
wherein
R1 is aroyl substituted with heterocyclic group which has a suitable substituent selected from the group consisting of
aryl having cyclo(lower)alkyloxy,
aryl having morpholinyl,
aryl having aryloxy(lower)alkoxy,
heterocyclic group having cyclo(lower)alkyl,
heterocyclic group having higher alkyl,
ar(lower)alkyl having lower alkoxy, and
cyclo(lower)alkyl which may have one or more suitable substituent(s);
aroyl substituted with heterocyclic group which has hydroxy and may have additional one or more suitable substituent(s);
aroyl substituted with piperidyl which has aryl having lower alkoxy;
aroyl substituted with thiadiazolyl which has a suitable substituent selected from the group consisting
of aryl having pentyl,
aryl having hexyl,
aryl having methoxy,
aryl having butoxy, and
aryl having higher alkoxy;
aroyl substituted with aryl which has aryl having pentyloxy;
aroyl substituted with piperazinyl which has 3-hexyloxyphenyl;
aroyl substituted with 1,2,3,6-tetrahydropyridyl which may have one or more suitable substituent(s);
aroyl substituted with thienyl which may have one or more suitable substituent(s);
aroyl substituted with furyl which may have one or more suitable substituent(s);
aroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s);
aroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s);
lower alkanoyl substituted with thiazolyl which may have one or more suitable substituent(s);
aroyl substituted with imidazothiadiazolyl which may have one or more suitable substituent(s);
aroyl substituted with isoxazolyl having halogen which may have one or more suitable substituent(s); or
4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl; and
R2 is hydroxy, hydroxysulfonyloxy or lower alkoxy, with proviso that
R2 is not hydroxysulfonyloxy, when R1 is 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl.
The new polypeptide compound [I] and a salt thereof can be prepared by the process as illustrated in the following reaction scheme. 
wherein R1 and R2 are as defined above,
Ra2 is hydroxysulfonyloxy,
Rb2 is hydroxy or
Rc2 is lower alkoxy.
The starting compound [IIb] and [IIc] or a salt thereof are novel and can be prepared by the following schemes. 
Wherein Rd2 is lower alkoxy.
Suitable salts of the object polypeptide compound [I] are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt;
a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,NI-dibenzylethylenediamine salt, etc.);
an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.);
an organic carboxylic sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows:
The term xe2x80x9clowerxe2x80x9d is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term xe2x80x9chigherxe2x80x9d is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable example of xe2x80x9cone or morexe2x80x9d may be the number of 1 to 6, in which the preferred one may be the number of 1 to 3.
Suitable example of xe2x80x9clower alkanoylxe2x80x9d may include straight or branched one such as formyl, acetyl, 2-methylacetyl, 2,2-dimethylacetyl, propionyl, butyryl, isobutyryl, pentanoyl, 2,2-dimethylpropionyl, hexanoyl, and the like.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d may include lower alkoxy as mentioned below, higher alkoxy as mentioned below, lower alkyl as mentioned below, higher alkyl as mentioned below, higher alkoxy(lower)alkyl, lower alkoxycarbonyl, oxo, aryl which may have one or more lower alkoxy, aryl which may have one or more higher alkoxy, aryl which may have one or more lower alkyl, aryl which may have one or more higher alkyl, aryl substituted with aryl which may have one or more lower alkoxy, aryl substituted with aryl which may have one or more higher alkoxy, aryl substituted with aryl which may have one or more lower alkyl, aryl substituted with aryl which may have one or more higher alkyl, aroyl which may have one or more lower alkoxy, aroyl which may have one or more higher alkoxy, aroyl which may have one or more lower alkyl, aroyl which may have one or more higher alkyl, heterocyclic group which may have one or more lower alkoxy, heterocyclic group which may have one or more higher alkoxy, aryl having heterocyclic(higher)alkoxy, heterocyclic group which may have aryl having higher alkoxy, heterocyclic group which may have aryl having lower alkoxy(higher)alkoxy, heterocyclic group which may have aryl having lower alkoxy, lower alkoxy(lower)alkyl, halo(lower)alkoxy, lower alkenyloxy, halo(higher)alkoxy, lower alkoxy(higher)alkoxy, aryl which may have one or more lower alkoxy(lower)alkoxy, heterocyclic group, aryl which may have one or more lower alkoxy(higher)alkoxy, aryl which may have one or more higher alkenyloxy, cyclo(lower)alkyl which may have aryl, aryl substituted with heterocyclic group which may have lower alkyl and oxo, cyclo(lower)alkyl which may have one or more lower alkyl, aryl which may have cyclo(lower)alkyl, aryl which may have heterocyclic group, and the like.
Suitable example of xe2x80x9clower alkoxyxe2x80x9d may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neo-pentyloxy, hexyloxy, isohexyloxy, and the like, in which the preferred one may be methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isohexyloxy.
Suitable example of xe2x80x9chigher alkoxyxe2x80x9d may include straight or branched one such as heptyloxy, octyloxy, 3,5-dimethyloctyloxy, 3,7-dimethyloctyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, and the like,
in which the preferred one may be (C7-C14)alkoxy, and the more preferred one may be heptyloxy and octyloxy.
Suitable example of xe2x80x9clower alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, and the like,
in which the preferred one may be methyl, pentyl, hexyl and isohexyl.
Suitable example of xe2x80x9chigher alkylxe2x80x9d may include straight or branched one having 7 to 20 carbon atoms, such as heptyl, octyl, 3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like,
in which the preferred one may be (C7-C14)alkyl, and the more preferred one may be heptyl, octyl, nonyl and decyl.
Suitable example of xe2x80x9carylxe2x80x9d and xe2x80x9carxe2x80x9d moiety may include phenyl which may have lower alkyl (e.g., phenyl, mesityl, tolyl, etc.), naphthyl, anthryl, and the like,
in which the preferred one may be phenyl and naphthyl.
Suitable example of xe2x80x9caroylxe2x80x9d may include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl, and the like,
in which the preferred one may be benzoyl and naphthoyl.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d moiety may include
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, tetrahydrofuran, tetrahydropyran, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
Suitable example of xe2x80x9chaloxe2x80x9d may include fluoro, chloro, bromo and iodo.
Suitable example of xe2x80x9clower alkenyloxyxe2x80x9d may include vinyloxy, 1-(or 2-)propenyloxy, 1-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or 4-)pentenyloxy, 1-(or 2- or 3- or 4- or 5-)hexenyloxy, and the like, in which the preferred one may be (C2-C6)alkenyloxy, and the most preferred one may be 5-hexenyloxy.
Suitable example of xe2x80x9chigher alkenyloxyxe2x80x9d may include (C7-C20)alkenyloxy, in which the preferred one may be 6-heptenyloxy and 7-octenyloxy.
Suitable example of xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which the preferred one may be cyclo(C4-C6)alkyl, and the most preferred one may be cyclohexyl.
Suitable example of xe2x80x9car(lower)alkylxe2x80x9d may include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, and the like, in which the preferred one may be phenyl(C1-C4)alkyl, and the most preferred one may be phenethyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic group which has a suitable substituent selected from the group consisting of aryl having cyclo(lower)alkyloxy, aryl having morpholinyl, aryl having aryloxy(lower)alkoxy, heterocyclic group having cyclo(lower)alkyl, heterocyclic group having higher alkyl, ar(lower)alkyl having lower alkoxy and cyclo(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of said xe2x80x9cheterocyclic groupxe2x80x9d moiety can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be xe2x80x9csaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)xe2x80x9d and xe2x80x9cunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s)xe2x80x9d, and the most preferred one may be piperidyl, piperazinyl and thiadiazolyl.
Suitable example of xe2x80x9caryl having cyclo(lower)alkyloxyxe2x80x9d moiety may be cyclopropyloxyphenyl, cyclobutyloxyphenyl, cyclopentyloxyphenyl, cyclohexyloxyphenyl, cyclopentyloxynaphthyl, cyclohexyloxynaphthyl, cyclohexyloxyanthryl, and the like, in which the preferred one may be phenyl having cyclo(C4-C6)alkyloxy, and the most preferred one may be cyclohexyloxyphenyl.
Suitable example of xe2x80x9caryl having morpholinylxe2x80x9d moiety may be 4-morpholinylphenyl, 3-morpholinylnaphthyl, 2-morpholinylanthryl, and the like, in which the preferred one may be morpholinylphenyl and the most preferred one may be morpholinophenyl.
Suitable example of xe2x80x9caryl having aryloxy(lower)alkoxyxe2x80x9d moiety may be phenoxymethoxyphenyl, phenoxyethoxyphenyl, phenoxypropoxyphenyl, phenoxybutoxyphenyl, phenoxypentyloxynaphthyl, phenoxyhexyloxyphenyl, naphthyloxymethoxyphenyl, naphthyloxyethoxynaphthyl, naphthyloxypropoxyphenyl, anthryloxybutoxynaphthyl, and the like, in which the preferred one may be phenoxy(C1-C4)-alkoxyphenyl, and the most preferred one may be phenoxypropoxyphenyl.
Suitable example of xe2x80x9cheterocyclic group having cyclo(lower)alkylxe2x80x9d moiety may be saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclopropyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclobutyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclopentyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclohexyl, and the like, in which the preferred one may be piperidyl having cyclo(C4-C6)alkyl, and the most preferred one may be piperidyl having cyclohexyl.
Suitable example of xe2x80x9cheterocyclic group having higher alkylxe2x80x9d moiety may be saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having heptyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having octyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having nonyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having decyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having undecyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having dodecyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having tridecyl, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having tetradecyl, and the like, in which the preferred one may be piperidyl having (C7-C14)alkyl, and the most preferred one may be piperidyl having octyl.
Suitable example of xe2x80x9car(lower)alkyl having lower alkoxyxe2x80x9d moiety may be methoxybenzyl, ethoxybenzyl, propoxybenzyl, butoxybenzyl, pentyloxybenzyl, pentyloxyphenethyl, hexyloxyphenethyl, pentyloxyphenylpropyl, hexyloxyphenylbutyl, pentyloxyphenylpentyl, hexyloxyphenylhexyl, and the like, in which the preferred one may be phenethyl having (C4-C6)alkoxy, and the most preferred one may be hexyloxyphenethyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9ccyclo(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be cyclo(lower)alkyl, and the more preferred one may be cyclo(C4-C6)alkyl, and the most preferred one may be cyclohexyl.
Suitable example of xe2x80x9ccyclo(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may be cyclo(lower)alkyl which may have cyclo(lower)alkyl or lower alkyl, in which the preferred one may be cyclo(C4-C6)alkyl having cyclo(C4-C6)-alkyl or (C4-C6)alkyl, and the most preferred one may be cyclohexyl having cyclohexyl or cyclohexyl having pentyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic group which has hydroxy and may have additional one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9cheterocyclic group xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic group which has hydroxy and may have additional one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be saturated 3 to 8-membered heterocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be piperidyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in said group may be aryl having lower alkoxy such as methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, pentyloxyphenyl, hexyloxyphenyl, pentyloxynaphthyl, hexyloxynaphthyl, hexyloxyanthryl, and the like, in which the preferred one may be phenyl having (C4-C6)alkoxy, and the most preferred one may be hexyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with piperidyl which has aryl having lower alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9carylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with piperidyl which has aryl having lower alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9caroyl substituted with piperidyl which has aryl having lower alkoxyxe2x80x9d may be benzoyl substituted with piperidyl which has hexyloxyphenyl, naphthoyl substituted with piperidyl which has hexyloxynaphthyl, and the like, in which the preferred one may be benzoyl substituted with piperidyl which has phenyl having (C4-C6)alkoxy, and the most preferred one may be benzoyl substituted with piperidyl which has hexyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with thiadiazolyl which has a suitable substituent selected from the group consisting of aryl having pentyl, aryl having hexyl, aryl having methoxy, aryl having butoxy and aryl having higher alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9carylxe2x80x9d moiety in the term of xe2x80x9caryl having pentyl, aryl having hexyl, aryl having methoxy, aryl having butoxy and aryl having higher alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9caroyl substituted with thiadiazolyl which has a suitable substituent selected from the group consisting of aryl having pentyl, aryl having hexyl, aryl having methoxy, aryl having butoxy and aryl having higher aloxyxe2x80x9d may be benzoyl substituted with thiadiazolyl which has a suitable substituent selected from the group consisting of pentylphenyl, hexylphenyl, methoxyphenyl, butoxyphenyl and heptyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with aryl which has aryl having pentyloxyxe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9carylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with aryl which has aryl having pentyloxyxe2x80x9d can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may e phenyl.
Suitable example of xe2x80x9caroyl substituted with aryl which has aryl having pentyloxylxe2x80x9d may be benzoyl substituted with phenyl which has pentyloxyphenyl, naphthoyl substituted with naphthyl which has pentyloxyphenyl, anthrylcarbonyl substituted with phenyl which has pentyloxynaphthyl, and the like, in which the preferred one may be benzoyl substituted with phenyl which has pentyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d in the term of xe2x80x9caroyl substituted with piperazinyl which has 3-hexyloxyphenylxe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9caroyl substituted with piperazinyl which has 3-hexyloxyphenylxe2x80x9d may be benzoyl substituted with piperazinyl which has 3-hexyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with 1,2,3,6-tetrahydropyridyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d in which the preferred one may be benzoyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with 1,2,3,6-tetrahydropyridyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have one or more lower alkoxy, and the more preferred one may be phenyl which may have a (C4-C6)alkoxy, and the most preferred one may be hexyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with thienyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d in the term of xe2x80x9caroyl substituted with thienyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have one or more lower alkoxy, and the more preferred one may be phenyl which may have a (C4-C6)alkoxy, and the most preferred one may be pentyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with furyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with furyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have one or more lower alkoxy, and the more preferred one may be phenyl which may have a (C4-C6)alkoxy, and the most preferred one may be pentyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9cheterocyclicxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclicxe2x80x9d moiety, in which the preferred one may be saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be piperazinyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have cyclo(lower)alkyl, and the more preferred one may be phenyl which has cyclo(C4-C6)alkyl, and the most preferred one may be cyclohexylphenyl.
Suitable example of xe2x80x9caroyl substituted with heterocyclic(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may be benzoyl substituted with heterocyclic(C1-C6)alkyl which may have phenyl which may have cyclo(C3-C6)alkyl, in which the preferred one may be benzoyl substituted with (C1-C4)alkyl having saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have phenyl which has cyclo(C4-C6)alkyl, and the most preferred one may be benzoyl substituted with piperazinylmethyl which has phenyl having cyclohexyl or benzoyl substituted with piperazinylethyl which has phenyl having cyclohexyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9car(lower)alkynylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s)xe2x80x9d may be phenylethynyl, phenylpropynyl, phenylbutynyl, naphthylpentynyl, phenylhexynyl, naphthylethynyl, anthrylpropynyl, and the like, in which the preferred one may be phenyl(C2-C4)alkynyl, and the most preferred one may be phenylethynyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be lower alkoxy, and the more preferred one may be (C4-C6)alkoxy, and the most preferred one may be pentyloxy.
Suitable example of xe2x80x9caroyl substituted with ar(lower)alkynyl which may have one or more suitable substituent(s)xe2x80x9d may be benzoyl substituted with phenyl(lower)alkynyl which may have lower alkoxy, in which the preferred one may be benzoyl substituted with phenyl-(C2-C4)alkynyl which has (C4-C6)alkoxy, and the most preferred one may be benzoyl substituted with phenylethynyl which has pentyloxy.
Suitable example of xe2x80x9clower alkanoylxe2x80x9d moiety in the term of xe2x80x9clower alkanoyl substituted with thiazolyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkanoylxe2x80x9d, in which the preferred one may be (C1-C4)alkanoyl, and the most preferred one may be formyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d in the term of xe2x80x9clower alkanoyl substituted with thiazolyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl substituted with aryl having lower alkoxy, and the more preferred one may be phenyl substituted with phenyl having (C4-C6)alkoxy, and the most preferred one may be phenyl substituted with pentyloxyphenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with imidazothiadiazolyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with imidazothiadiazolyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have one or more lower alkoxy or aryl substituted with aryl, and the more preferred one may be aryl having (C2-C6)alkoxy or aryl having phenyl, and the most preferred one may be phenyl having pentyloxy, phenyl having ethoxy or phenyl having phenyl.
Suitable example of xe2x80x9caroyl substituted with imidazothiadiazolyl which may have one or more suitable substituent(s)xe2x80x9d may be benzoyl substituted with imidazothiadiazolyl which has phenyl having (C2-C6)alkoxy or benzoyl substituted with imidazothiadiazolyl which has aryl having phenyl, and the most preferred one may be benzoyl substituted with imidazothiadiazolyl which has phenyl having pentyloxy, benzoyl substituted with imidazothiadiazolyl which has phenyl having ethoxy or benzoyl substituted with imidazothiadiazolyl which has phenyl having phenyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety in the term of xe2x80x9caroyl substituted with isoxazolyl having halogen which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9caroylxe2x80x9d, in which the preferred one may be benzoyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caroyl substituted with isoxazolyl having halogen which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9csuitable substituent(s)xe2x80x9d, in which the preferred one may be aryl which may have lower alkoxy, the preferred one may be phenyl which has (C4-C6)-alkoxy, and the most preferred one may be phenyl having pentyloxy.
Suitable example of xe2x80x9caroyl substituted with isoxazolyl having halogen which may have one or more suitable substituent(s)xe2x80x9d may be benzoyl substituted with isoxazolyl having chloro which has phenyl having (C4-C6)alkoxy, and the most preferred one may be benzoyl substituted with isoxazolyl having chloro which has phenyl having pentyloxy.
The processes for preparing the object polypeptide compound [I] and the starting compounds [IIb] and [IIc] or a salt thereof of the present invention are explained in detail in the following.
Process 1
The object polypeptide compound [I] or a salt thereof can be prepared by reacting the compound [II] or its reactive derivative at the amino group or a salt thereof with the compound [III] or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the carboxy group of the compound [III] may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivaric acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.]; or aromatic carboxylic acid [e.g., benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester [e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl 
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachloropentyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the mind of the compound [III] to be used.
Suitable salts of the compound [III] and its reactive derivative can be referred to the ones as exemplified for the object polypeptide compound [I].
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound [III] is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-N-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, methanesulfonyl chloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
The starting compound [IIa] is a known compound. It can be prepared by fermentation and synthetic processes disclosed in EP 0462531 A2.
A culture of Coleophoma sp. F-11899, which is used in said fermentation process, has been deposited with National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology (former name Fermentation Research Institute Agency of Industrial Science and Technology) (1-3, Higashi 1-chome, Tsukuba-shi, IBARAKI 305, JAPAN) on Oct. 26, 1989 under the number of FERM BP-2635.
Process 2
The compound [Ib] or a salt thereof can be prepared by subjecting the compound [Ia] or its reactive derivative at the sulfonic acid group or a salt thereof to hydrolysis reaction of the sulfonic acid group.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, or the like.
Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen, chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid, trifluoroacetic acid, etc.], or the like is preferably carried out in the presence of cation trapping agents [e.g., anisole, phenol, etc.].
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process 3
The compound [Ic] or a salt thereof can be prepared by subjecting the compound [Ib] or its reactive derivative at the hydroxy group or a salt thereof with the diazo compound [e.g., diazomethane, phenyldiazomethane, diphenyldiazomethane, xcex2-diazopropionic acid, etc.] or a salt thereof to alkylation reaction of the hydroxy group.
This reaction is usually carried out in the solvent such as water, alcohol [e.g., methanol, ethanol, etc.], benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether, acetonitrile or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction may be usually carried out in the presence of an acid including Lewis acid.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide, potassium, hydroxide, etc.], an alkali metal hydrogencarbonate [e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.], alkali metal carbonate [e.g., sodium carbonate, potassium carbonate, etc.], tri(lower)alkylamine [e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.], alkali metal hydride [e.g., sodium hydride, etc.], alkali metal (lower)alkoxide [e.g. sodium methoxide, sodium ethoxide, etc.], pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
When the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.
Process A
The starting compound [IIb] or a salt thereof can be prepared by subjecting the compound [IIa] or its reactive derivative at the sulfonic acid group or a salt thereof to hydrolysis reaction of the sulfonic acid group.
This reaction can be carried out in a similar manner to that of Process 2 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g., base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2.
Process B
The starting compound [IIc] or a salt thereof can be prepared by subjecting the compound [IIb] or its reactive derivative at the hydroxy group or a salt thereof with the diazo compound [e.g., diazomethane, phenyldiazomethane, diphenyldiazomethane, xcex2-diazopropionic acid, etc.] or a salt thereof to alkylation reaction of the hydroxy group.
This reaction can be carried out in a similar manner to that of Process 3 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g., base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 3.
The compounds obtained by the above Processes 1 to 3 and Processes A and B can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, high-performance liquid chromatography (HPLC), reprecipitation, or the like.
The compounds obtained by the above Processes 1 to 3 and Processes A and B may be obtained as its hydrate, and its hydrate is included within the scope of this invention.
It is to be noted that each of the object compound [I] may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
In order to show the usefulness of the polypeptide compound [I] of the present invention, the biological data of the representative compound is explained in the following.
Test (Antimicrobial Activity)
In vitro antimicrobial activity of the compound of Example 15 disclosed later was determined by the two-fold agar-plate dilution method as described below.
Test Method
One loopful of an overnight culture of each test microorganism in Sabouraud broth containing 2% Glucose (105 viable cells per ml) was streaked on yeast nitrogen base dextrose agar (YNBDA) containing graded concentrations of the object polypeptide compound [I], and the minimal inhibitory concentration (MIC) was expressed in terms of xcexcg/ml after incubation at 30xc2x0 C. for 24 hours.
Test Result
From the test result, it is realized that the object polypeptide compound [I] of the present invention has an antimicrobial activity (especially, antifungal activity).
The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object polypeptide compound [I] or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator.
The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsules, or suppositories; creams; ointments; aerosols; powders for insufflation; in a liquid form such as solutions, emulsions, or suspensions for injection; ingestion; eye drops; and any other form suitable for use. And, if necessary, there may be included in the above preparation auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring agents; perfumes or buffer; or any other commonly may be used as additives.
The object polypeptide compound [I] or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process or condition of diseases.
For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, pulmonary, oral administration, or insufflation. While the dosage of therapeutically effective amount of the object polypeptide compound [I] varies form and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-20 mg of the object polypeptide compound [I] per kg weight of human being in the case of intramuscular administration, a daily dose of 0.1-20 mg of the object polypeptide compound [I] per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the object polypeptide compound [I] per kg weight of human being is generally given for treating or preventing infectious diseases.
Especially in case of the treatment of prevention of Pneumocystis carinii infection, the followings are to be noted.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized as powders which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation aerosol, which may be formulated as a suspension or solution of compound in suitable propellants such as fluorocarbons or hydrocarbons.
Because of desirability to directly treat lung and bronchi, aerosol administration is a preferred method of administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities.
Alternatively, parenteral administration may be employed using drip intravenous administration.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
Preparation 1
To a suspension of sodium hydride (60% suspension in mineral oil) (1.18 g) in dimethylformamide (25 ml) was added 1-acetyl-4-(4-hydroxyphenyl)piperazine (5 g) and bromocyclohexane (5.59 ml) and stirred for 1 hour at 100xc2x0 C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetyl-4-(4-cyclohexyloxyphenyl)piperazine (0.92 g).
Preparation 2
A solution of 3-[2-(4-morpholinophenylamino)ethyl]-2-oxazolidone (5 g) in 30% hydrobromic acid in acetic acid (35 ml) was stirred for 24 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and added to ethanol (35 ml). The solution was refluxed for 8 hours and pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-morpholinophenyl)-piperazine dihydrobromide (7.42 g).
IR (KBr): 1608.3, 1521.6, 1259.3, 889.0 cmxe2x88x921 
NMR (D2O, xcex4): 3.3-3.8 (12H, m), 4.1-4.2 (4H, m), 7.24 (2H, d, J=9.3 Hz), 7.58 (2H, d, J=9.3 Hz)
APCI-MASS: m/z=248 (M+H)+
Preparation 3
To a solution of 1-tert-butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (6.856 g) in dichloromethane (34 ml) was added trifluoroacetic acid (17 ml) and stirred for 30 minutes at 4xc2x0 C. The reaction mixture was adjusted to pH 12 with 2M aqueous NaOH. The organic layer was separated, washed with water and dried over magnesium sulfate and evaporated under reduced pressure to give 4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropiridine (3.59 g)
IR (KBr): 3263.0, 1604.5, 1511.9, 1251.6, 842.7 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.6-1.9 (3H, m), 2.3-2.5 (2H, m), 3.10 (2H, t, J=5.7 Hz), 3.4-3.6 (2H, m), 3.95 (2H, t, J=6.5 Hz), 6.0-6.1 (1H, m), 6.85 (2H, d, J=8.9 Hz), 7.30 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=260 (M+H)+
Preparation 4
A solution of 4-[4-(3-hydroxyphenyl)piperazin-1-yl]benzoic acid dihydrobromide (2.396 g) in a mixture of 5% NaOH aq. (16.7 ml) and dimethylsulfoxide (33.3 ml) was stirred for 30 minutes at 80xc2x0 C. Then, 1-bromohexane (0.88 ml) was added thereto and stirred for 8 hours at 80xc2x0 C. The reaction mixture was added to water and adjusted to pH 2.0 with 1N HCl. The produced precipitate was collected by filtration and dried under reduced pressure to give 4-[4-(3-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (3.74 g).
IR (KBr): 1670.1, 1602.6, 1236.1, 1189.9 cm-xe2x88x921 
NMR (DMSO-d6, xcex4): 0.88 (3H t, J=6.9 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.2-3.5 (8H, m), 3.93 (2H, t, J=6.4 Hz), 6.38 (1H, d, J=8.0 Hz), 6.49 (1H, s), 6.55 (1H, d, J=8.0 Hz), 7.02 (2H, d, J=9.0 Hz), 7.12 (1H, dd, J=8.0 Hz), 7.79 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=383 (M+H)+
Preparation 5
To a solution of methyl 4-[5-[N-(tert-butoxycarbonyl)-piperidin-4-yl]-1,3,4-thiadiazol-2-yl]benzoate (1.28 g) in dichloromethane (12 ml) was added trifluoroacetic acid (25 ml) at 0xc2x0 C. and the reaction mixture was stirred for 1 hour at room temperature. The solvents were removed under reduced pressure. The precipitate was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give 4-[5-(4-methoxycarbonylphenyl)-1,3,4-thiadiazol-2-yl]piperidinium trifluoroacetate (1.31 g).
IR (KBr): 2956, 2840, 1722, 1673, 1436, 1282, 1211, 1180, 1124 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.0-2.2 (2H, m), 2.30 (2H, d, J=12.0 Hz), 3.0-3.2 (2H, m), 3.4-3.7 (3H, m), 3.90 (3H, s), 8.12 (4H, s), 8.6-9.0 (2H, br)
APCI-MASS: m/z=304 (M+H)+ free.
Preparation 6
To a suspension of ethyl 4-bromobenzoate (1.37 g), (4-n-pentyloxyphenyl)acetylene (565 mg), triphenylphosphine (16 mg) and copper(I) iodide (6 mg) in triethylamine (10 ml) and pyridine (4 ml) was added palladium(II) chloride bis(triphenylphosphine) (21 mg) and the reaction mixture was stirred for 24 hours at 80xc2x0 C. After cooling, the precipitate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was taken up to dichloromethane, and the solution was washed successively with 1N HCl, water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give ethyl 4-(4-n-pentyloxyphenylethynyl)benzoate (355 mg).
IR (KBr): 2940, 2869, 1706, 1515, 1274, 1103 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.93 (3H, t, J=7.0 Hz), 1.3-1.6 (7H, m), 1.7-1.9 (2H, m), 3.97 (2H, t, J=6.5 Hz), 4.38 (2H, q, J=7.1 Hz), 6.87 (2H, d, J=8.9 Hz), 7.44 (2H, d, J=8.9 Hz), 7.51 (2H, d, J=8.5 Hz), 8.01 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=337 (M+H)+
Preparation 7
To a solution of 4-(4-n-pentyloxyphenyl)benzamide (1.0 g) in tetrahydrofuran (10 ml) was added Lawesson""s reagent (1.0 g). The reaction mixture was refluxed for 3 hours and diluted with dichloromethane. The insoluble residue was removed by filtration and the filtrate was evaporated to dry. To a solution of the residue in tetrahydrofuran (10 ml) was added ethyl bromopyruvate (887 mg). The mixture was stirred for 3 hours at room temperature, diluted with dichloromethane (100 ml) and washed with water and brine. The separated organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile and the solid was collected by filtration and dried under reduced pressure to give ethyl 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-vas thiapentanoate (895 mg).
IR (KBr): 3120, 2954, 2863, 1753, 1591, 1498, 1471 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.1 Hz), 1.4-1.6 (4H, m), 1.7-1.9 (2H, m), 3.55 (1H, d, J=12.2 Hz), 3.9-4.1 (3H, m), 4.2-4.4 (2H, m), 4.47 (1H, s), 6.97 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.5 Hz), 7.92 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=414 (M+H)+
Preparation 8
To a suspension of ethyl 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-thiapentanoate (0.87 g) in tetrahydrofuran (16 ml) and ethanol (8 ml) was added 10% NaOH aq. (1.32 ml). The mixture was refluxed for 1 hour and adjusted to pH 2.0 with 1N HCl. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give crude 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-thiapentanoic acid. A suspension of crude 4-imino-2-oxo-4-[4-(4-n-pentyloxyphenyl)phenyl]-3-thiapentanoic acid obtained in ethanol (50 ml) was refluxed for 4 hours. After cooling, the precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give 2-[4-(4-n-pentyloxyphenyl)phenyl]-4-thiazolecarboxylic acid (353 mg).
IR (KBr): 2958, 2935, 1687, 1602, 1465, 1253, 1199 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.91 (3H, t, J=6.9 Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m), 4.02 (2H, t, J=6.5 Hz), 7.04 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.5 Hz), 8.02 (2H, d, J=8.5 Hz), 8.49 (1H, s), 13.1 (1H, br s)
APCI-MASS: m/z=368 (M+H)+
Preparation 9
To a suspension of 4-n-pentyloxybenzoic acid (5.0 g) in toluene was added oxalyl chloride (15 ml) and N,N-dimethylformamide (0.1 ml) and the mixture was stirred for 2 hours at room temperature. The solvents were evaporated under reduced pressure to give crude 4-n-pentyloxybenzoyl chloride. To a suspension of N,O-dimethylhydroxylamine a hydrochloride (3.51 g) and pyridine (5.82 ml) in tetrahydrofuran (25 ml) was added the solution of crude 4-n-pentyloxybenzoyl chloride in tetrahydrofuran (25 ml) dropwise at 0xc2x0 C. and the mixture was stirred for 3 hours at room temperature. To the reaction mixture 1N HCl was added and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give N-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.63 g).
NMR (CDCl3, xcex4): 0.94 (3H, t, J=7.0 Hz), 1.3-1.6 (4H, m), 1.7-1.9 (2H, m), 3.35 (3H, s), 3.56 (3H, s), 3.99 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.9 Hz), 7.71 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=252 (M+H)+
Preparation 10
To a solution of N-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.52 g) in tetrahydrofuran (25 ml) was added 1.6 molar tetrahydrofuran solution of vinylmagnesium bromide (25.5 ml) at xe2x88x9250xc2x0 C. dropwise and the mixture was stirred for 3 hours at xe2x88x9220xc2x0 C. To the mixture was added 1N HCl (50 ml) dropwise and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate)=(8/2) to give 1-(4-n-pentyloxyphenyl)acrolein (2.40 g).
IR (KBr): 2956, 2935, 2867, 1672, 1600, 1510, 1255, 1170 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=7.1 Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m), 4.03 (2H, t, J=6.5 Hz), 5.86 (1H, dd, J=10.5 and 1.9 Hz), 6.42 (1H, dd, J=17.0 and 1.9 Hz), 6.94 (2H, d, J=8.9 Hz), 7.21 (1H, dd, J=17.0 and 10.9 Hz), 7.95 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=219 (M+H)+
Preparation 11
A suspension of 1-(4-n-pentyloxyphenyl)acrolein (2.38 g), methyl 4-formylbenzoate (1.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride and triethylamine (0.91 ml) in ethanol (10 ml) was refluxed for 18 hours. After cooling, the solvents were removed under reduced pressure. The solids were taken up in 1N HCl and extracted with dichloromethane. The organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration and dried under reduced pressure to give 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (3.41 g).
IR (KBr): 2956, 2867, 1722, 1672, 1606, 1284, 1257, 1110 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=7.0 Hz), 1.5-1.7 (4H, m), 1.8-2.0 (2H, m), 3.44 (4H, s), 3.95 (3H, s), 4.03 (2H, t, J=6.5 Hz), 6.94 (2H, d, J=8.9 Hz), 7.99 (2H, d, J=8.9 Hz), 8.08 (2H, d, J=8.7 Hz), 8.14 (2H, d, J=8.7 Hz)
APCI-MASS: m/z=383 (M+H)+
Preparation 12
A suspension of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl) butane-1,4-dione (765 mg) and phosphorus pentasulfide (533 mg) in tetrahydrofuran (10 ml) was stirred for 6 hours at room temperature, poured into water and stirred for 1 hour. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)thiophen-2-yl]benzoate (668 mg).
IR (KBr): 2956, 2935, 2867, 1722, 1604, 1438, 1284, 1112, 1022 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=6.9 Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m), 3.93 (3H, s), 3.99 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.8 Hz), 7.19 (1H, d, J=3.8 Hz), 7.37 (1H, d, J=3.8 Hz), 7.55 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=8.5 Hz), 8.04 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=381 (M+H)+
Preparation 13
A solution of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl)butane-1,4-dione (765 mg) and p-toluenesulfonic acid monohydrate (8 mg) in toluene (10 ml) was refluxed for 6 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure and the precipitate was triturated with methanol, collected by filtration, washed with methanol and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)furan-2-yl]benzoate (665 mg).
IR (KBr): 2956, 2933, 1720, 1284, 1253, 1176, 1110 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=6.9 Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m), 3.93 (3H, s), 3.99 (2H, t, J=6.5 Hz), 6.62 (1H, d, J=3.5 Hz), 6.85 (1H, d, J=3.5 Hz), 6.94 (2H, d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.5 Hz), 8.05 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=365 (M+H)+
Preparation 14
A mixture of 4-cyclohexylcyclohexanone (1.54 g), 1-(4-ethoxycarbonylphenyl)piperazine (2 g) and titanium(IV) isopropoxide (3.18 ml) was stirred at room temperature. After 1 hour, the IR spectrum of the mixture showed no ketone band, and the viscous solution was diluted with absolute ethanol (8.5 ml). Sodium cyanoborohydride (0.343 g) was added, and the solution was stirred for 3 hours. Water (3 ml) was added with stirring, and the resulting in organic precipitate was filtered and washed with ethanol. The filtrate was extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the less polar compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(cis-4-cyclohexylcyclohexyl)piperazin-1-yl]benzoate (692 mg) as byproduct. The fractions containing the more polar compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(trans-4-cyclohexylcyclohexyl)piperazin-1-yl]benzoate (587 mg).
Trans Isomer
IR (KBr): 2931.3, 1708.6, 1606.4, 1234.2 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.80-1.5 (12H, m), 1.36 (3H, t, J=7.1 Hz), 1.5-2.1 (8H, m), 2.40 (1H, m), 2.7-2.9 (4H, m), 3.3-3.5 (4H, m), 4.33 (2H, q, J=7.1 Hz), 6.86 (2H, d, J=9.1 Hz), 7.92 (2H, d, J=9.1 Hz)
APCI-MASS: m/z=m/z=399 (M+H)+
Cis Isomer
IR (KBr): 2925.5, 1706.7, 1606.4, 1282.4 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.8-1.9 (20H, m), 1.36 (2H, t, J=7.1 Hz), 2.25 (1H, m), 2.6-2.8 (4H, m), 3.2-3.5 (4H, m), 4.33 (2H, q, J=7.1 Hz), 6.85 (2H, d, J=9.1 Hz), 7.92 (2H, d, J=9.1 Hz)
APCI-MASS: m/z=399 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 14.
Preparation 15
4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]benzonitrile.
IR (KBr): 2931.3, 2215.8, 1606, 1515.8, 1178.3 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.0-2.6 (23H, m), 2.65-2.95 (2H, m), 2.95-3.25 (2H, m), 3.8-4.0 (2H, m), 6.83 (2H, d, J=8.9 Hz), 7.46 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=352 (M+H)+
Preparation 16
To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran (10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) in tetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature. Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone (4.12 g) and stirred for 2 hours under ice-cooling. The reaction was quenched with saturated NH4Cl aq. and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the object compound were collected and evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g).
IR (KBr): 3430, 1675.8, 1247.7 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.6 Hz), 1.2-1.85 (11H, m), 1.85-2.1 (2H, m), 3.2-3.5 (2H, m), 3.94 (2H, t, J=6.5 Hz), 4.05-4.2 (2H, m), 5.15 (2H, s), 6.87 (2H, d, J=8.8 Hz), 7.3-7.5 (7H, m)
APCI-MASS: m/z=394 (M+Hxe2x88x92H2O)+
The following compound was obtained according to a similar manner to that of Preparation 16.
Preparation 17
1-tert-Butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine
IR (KBr): 3434.6, 2954.4, 2931.3, 1693.2, 1670.1, 1172.5 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.5 (8H, m), 1.49 (9H, s), 1.65-1.85 (4H, m), 1.85-2.1 (2H, m), 3.1-3.35 (2H, m), 4.10 (2H, t, J=7.1 Hz), 4.17 (1H, br s), 6.88 (2H, d, J=8.9 Hz), 7.37 (2H, d, J=8.9 Hz).
Preparation 18
To a solution of 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (1.4 g) in methanol (28 ml) was added dry 10% palladium on carbon (0.7 g) and stirred for 6 hours under hydrogen atmosphere. The palladium on carbon was filtered off, and the filtrate was evaporated under reduced pressure to give 4-(4-hexyloxyphenyl)-4-hydroxypiperidine (0.74 g).
IR (KBr): 3332.4, 1610.3, 1513.8, 1249.6 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.6-1.9 (4H, m), 1.9-2.19 (2H, m), 2.35 (2H, br s), 2.85-3.25 (4H, m), 3.95 (2H, t, J=6.5 Hz), 6.87 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz)
APCI-MASS: m/z=260 (M+Hxe2x88x92H2O)+
The following compounds [Preparations 19 and 20] were obtained according to a similar manner to that of Preparation 18.
Preparation 19
4-[4-(4-Hexyloxyphenyl)-4-hydroxypiperidin-1-yl]benzoic acid
IR (KBr): 3548.4, 1668.1, 1600.6, 1187.9 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.5 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (4H, m), 1.8-2.1 (2H, m), 3.1-3.4 (2H, m), 3.7-3.85 (2H, m), 3.92 (2H, t, J=6.5 Hz), 4.97 (1H, s), 6.85 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=9.0 Hz), 7.35 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=9.0 Hz), 12.2 (1H, s)
APCI-MASS: m/z=398 (M+H)+
Preparation 20
Ethyl 4-[4-(4-hexyloxyphenyl)piperidin-1-yl]benzoate
IR (KBr): 1700.9, 1606.4, 1511.9, 1274.7, 1178.3 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.40 (3H, t, J=7.2 Hz), 1.7-2.1 (6H, m), 2.5-2.8 (1H, m), 2.8-3.05 (2H, m), 3.93 (2H, t, J=6.5 Hz), 3.9-4.1 (2H, m), 4.32 (2H, q, J=7.2 Hz), 6.84 (2H, d, J=8.7 Hz), 6.90 (2H, d, J=9.0 Hz), 7.12 (2H, d, J=8.7 Hz), 7.92 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=410 (M+H)+
Preparation 21
To a solution of methyl 3-(4-n-hexyloxyphenyl)propionate (1.18 g) in ethanol (10 ml) was added hydrazine monohydrate (1.08 ml) and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure. Water was added and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give 3-(4-n-hexyloxyphenyl)propionohydrazide (0.92 g).
IR (KBr): 3317, 2929, 1625, 1513, 1245 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.4 Hz), 1.3-1.5 (6H, m), 1.6-1.8 (2H, m), 2.26 (2H, t, J=7.7 Hz), 2.72 (2H, t, J=7.7 Hz), 3.90 (2H, t, J=6.5 Hz), 4.14 (2H, d, J=4.2 Hz), 6.80 (2H, d, J=8.6 Hz), 7.07 (2H, d, J=8.6 Hz), 8.93 (1H, t, J=4.2 Hz)
APCI-MASS: m/z=265 (M+H)+
The following compounds [Preparations 22 and 23] were obtained according to a similar manner to that of Preparation 21.
Preparation 22
N-(tert-Butoxycarbonyl)isonipecotinohydrazide
IR (KBr): 3320, 2979, 2942, 2846, 1691, 1629, 1527, 1432, 1230, 1178 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.39 (9H, s), 1.3-1.7 (4H, m), 2.1-2.3 (1H, m), 2.69 (2H, t, J=11.9 Hz), 3.93 (2H, d, J=13.2 Hz), 4.15 (2H, s), 8.99 (1H, s)
APCI-MASS: m/z=144 (Mxe2x88x92Boc)+
Preparation 23
4-(3-Phenoxypropyloxy)benzohydrazide
IR (KBr): 3297, 3182, 2948, 1650, 1502, 1305, 1253 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.18 (2H, tt, J=6.2 and 6.2 Hz), 4.12 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.2 Hz), 4.41 (2H, s), 6.9-7.1 (5H, m), 7.2-7.4 (2H, m), 7.79 (2H, d, J=8.8 Hz), 9.60 (1H, s)
APCI-MASS: m/z=287 (M+H)+
Preparation 24
To a suspension of 1-acetyl-4-(4-hydroxyphenyl) piperazine (20 g) and potassium bicarbonate (12.55 g) in dimethylsulfoxide (200 ml) was added 1-bromohexane (19.12 ml) and stirred for 24 hours at 80xc2x0 C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over is magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetyl-4-(4-hexyloxyphenyl)piperazine (14.5 g).
IR (KBr): 1621.8, 1513.8, 1251.6, 825.4 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.4 Hz), 1.25-1.55 (6H, m), 1.65-1.85 (2H, m), 2.13 (3H, s), 3.02 (2H, t, J=5.2 Hz), 3.04 (2H, t, J=5.2 Hz), 3.61 (2H, t, J=5.2 Hz), 3.76 (2H, t, J=5.2 Hz), 3.91 (2H, t, J=6.5 Hz), 6.83 (2H, d, J=9.1 Hz), 6.89 (2H, d, J=9.1 Hz).
The following compounds [Preparations 25 to 27] were obtained according to a similar manner to that of Preparation 24.
Preparation 25
4-[4-(4-Hexyloxyphenyl)piperazin-1-yl]benzonitrile
IR (KBr): 2212.0, 1602.6, 1510.0, 1247.7, 827.3 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.65-1.9 (2H, m), 3.1-3.3 (4H, m), 3.4-3.6 (4H, m), 3.92 (2H, t, J=6.5 Hz), 6.8-7.0 (6H, m), 7.52 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=364 (M+H)+
Preparation 26
Methyl 4-(3-phenoxypropyloxy)benzoate
IR (KBr): 2944, 2885, 1722, 1604, 1500, 1247 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.28 (2H, tt, J=6.0 and 6.0 Hz), 3.88 (3H, s), 4.16 (2H, t, J=6.0 Hz), 4.21 (2H, t, J=6.0 Hz), 6.8-7.0 (5H, m), 7.2-7.4 (2H, m), 7.98 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=287 (M+H)+
Preparation 27
Methyl 4-[5-(1-n-octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]benzoate
IR (KBr): 2925, 2852, 1714, 1440, 1278 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.89 (3H, t, J=6.5 Hz), 1.2-1.4 (10H, m), 1.4-2.4 (10H, m), 3.0-3.1 (2H, m), 3.2-3.3 (1H, m), 3.95 (3H, s), 8.01 (2H, d, J=8.6 Hz), 8.13 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=416 (M+H)+
Preparation 28
A solution of 1-acetyl-4-(4-hexyloxyphenyl)piperazine (14 g) in 1N HCl was refluxed for 5 hours. The reaction mixture was adjusted to pH 8 with saturated Na2CO3 aq. and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added ethyl acetate and 4N HCl in ethyl acetate (23 ml) and stirred for 1 hour. The resulting precipitate was collected by filtration to give 1-(4-hexyloxyphenyl)piperazine dihydrochloride (8.669 g).
IR (KBr): 1604.5, 1513.8, 1259.3 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.874 (3H, t, J=6.6 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.2-3.55 (8H, m), 3.92 (2H, t, J=6.4 Hz), 6.92 (2H, d, J=9.1 Hz), 7.15 (2H, d, J=9.1 Hz), 8.27 (1H, br s), 9.61 (2H, br s)
APCI-MASS: m/z=263 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 28.
Preparation 29
1-(4-Cyclohexyloxyphenyl)piperazine dihydrochloride
Preparation 30
To a suspension of 1-(4-hexyloxyphenyl)piperazine dihydrochloride (0.914 g) and potassium bicarbonate (0.564 g) in dimethylsulfoxide (5 ml) was added ethyl p-fluorobenzoate (0.2 ml) and stirred for 10 hours at 150xc2x0 C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (0.347 g).
IR (KBr): 1710.6, 1606.4, 1511.9, 1286.3, 1224.6 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.55 (6H, m), 1.37 (3H, t, J=7.1 Hz), 1.65-1.85 (2H, m), 3.1-3.25 (4H, m), 3.4-3.55 (4H, m), 3.92 (2H, t, J=6.5 Hz), 4.33 (2H, q, J=7.1 Hz), 6.8-7.0 (6H, m), 7.95 (2H, d, J=9.0 Hz).
The following compounds [Preparations 31 to 38] were obtained according to a similar manner to that of Preparation 30.
Preparation 31
Methyl 4-[4-(4-cyclohexylphenyl)piperazin-1-yl]methylbenzoate
IR (KBr): 2925.5, 1720.2, 1276.6, 1108.9 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.1-2.0 (10H, m), 2.42 (1H, m), 2.5-2.7 (4H, m), 3.1-3.3 (4H, m), 3.61 (2H, s), 3.91 (3H, s), 6.85 (2H, d, J=8.7 Hz), 7.10 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.2 Hz), 8.00 (2H, d, J=8.2 Hz).
Preparation 32
Ethyl 4-[4-(4-cyclohexyloxyphenyl)piperazin-1-yl]benzoate
Preparation 33
3-[2-(4-Morpholinophenylamino)ethyl]-2-oxazolidone
IR (KBr): 3330.5, 1740, 1523.5, 1118.5 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.9-3.2 (4H, m), 3.2-3.7 (4H, m), 3.60 (2H, dd, J=8.3 and 6.5 Hz), 3.8-4.0 (4H, m), 4.29 (2H, dd, J=8.9 and 7.1 Hz), 6.5-6.7 (2H, m), 6.8-7.0 (2H, m)
APCI-MASS: m/z=292 (M+H)+
Preparation 34
4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzonitrile
IR (KBr): 2210.0, 1600.6, 1511.9, 1234.2 cmxe2x88x921 
NMR (CDCl3, xcex4): 3.2-3.15 (4H, m), 3.15-3.3 (4H, m), 3.4-3.55 (4H, m), 3.8-3.9 (4H, m), 6.8-7.0 (6H, m), 7.52 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=349 (M+H)+
Preparation 35
Diphenylmethyl 4-[4-(4-hexyloxyphenyl)-4-hydroxypiperidin-1-yl]benzoate
IR (KBr): 3463.5, 1681.6, 1604.5, 1184.1 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.65-1.95 (4H, m), 2.0-2.3 (2H, m), 3.3-3.5 (2H, m), 3.65-3.85 (2H, m), 3.95 (2H, t, J=6.5 Hz), 6.88 (2H, d, J=8.9 Hz), 6.8-7.0 (2H, m), 7.09 (1H, s), 7.2-7.5 (10H, m), 8.03 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=564 (M+H)+
Preparation 36
Ethyl 4-[4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl]benzoate
IR (KBr): 2931.3, 1706.7, 1608.3, 1515.8 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.37 (3H, t, J=7.1 Hz), 1.7-1.9 (2H, m), 2.67 (2H, m), 3.63 (2H, t, J=5.6 Hz), 3.96 (2H, m, J=6.5 Hz), 3.9-4.1 (2H, m), 4.32 (2H, q, J=7.1 Hz), 6.0-6.1 (1H, m), 7.34 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz)
FAB-MASS: m/z=406 (M+H)+
Preparation 37
4-[4-(3-Methoxyphenyl)piperazin-1-yl]benzonitrile
IR (KBr): 2829.1, 2213.9, 1604.5, 1174.4 cmxe2x88x921 
NMR (CDCl3, xcex4): 3.3-3.4 (4H, m), 3.4-3.55 (4H, m), 3.81 (3H, s), 6.46 (1H, d, J=9.0 Hz), 6.49 (1H, s), 6.56 (1H, d, J=9.0 Hz), 6.90 (2H, d, J=9.0 Hz), 7.13 (1H, dd, J=9.0 Hz), 7.52 (2H, d, J=9.0 Hz).
Preparation 38
4-[4-(Piperidin-4-yl)piperidin-1-yl]benzonitrile
IR (KBr): 3332.4, 2212.0, 1602.6, 1513.8, 1178 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.0-1.5 (6H, m), 1.6-2.0 (4H, m), 1.91 (1H, s), 2.5-2.7 (2H, m), 2.7-2.9 (2H, m), 3.0-3.2 (2H, m), 3.8-4.0 (2H, m), 6.84 (2H, d, J=9.0 Hz), 7.45 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=270 (M+H)+
Preparation 39
A solution of 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]-benzonitrile (0.582 g) in the mixture of conc. HCl (5.8 ml) and acetic acid (2.9 ml) was refluxed for 3 hours. The reaction mixture was pulverized with water (25 ml). The precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (0.51 g).
IR (KBr): 1726.0, 1699.0, 1606.4, 1511.9 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.88 (3H, t, J=6.5 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.5-3.9 (8H, m), 4.00 (2H, t, J=6.4 Hz), 7.07 (2H, d, J=8.9 Hz), 7.09 (2H, d, J=8.9 Hz), 7.61 (2H, d, J=8.9 Hz), 7.84 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=383 (M+H)+
The following compounds [Preparations 40 to 42] were obtained according to a similar manner to that of Preraration 39.
Preparation 40
4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzoic acid dihydrochloride
IR (KBr): 1706.7, 1602.6, 1513.8, 1232.3 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.9-3.0 (4H, m), 3.1-3.2 (4H, m), 3.3-3.5 (4H, m), 3.65-3.8 (4H, m), 6.87 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 7.02 (2H, d, J=9.0 Hz), 7.79 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=368 (M+H)+
Preparation 41
4-[4-(3-Hydroxyphenyl)piperazin-1-yl]benzoic acid dihydrobromide
IR (KBr): 3183.9, 1679.7, 1604.5, 1232.3 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 3.3-3.7 (8H, m), 6.45 (1H, d, J=7.9 Hz), 6.62 (1H, d, J=7.9 Hz), 6.68 (1H, s), 7.04 (2H, d, J=9.0 Hz), 7.13 (1H, dd, J=7.9 Hz), 7.81 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=299 (M+H)+
Preparation 42
4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]benzoic acid dihydrobromide
IR (KBr): 1668.1, 1606, 1186 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.0-2.3 (21H, m), 2.7-4.1 (8H, m), 6.94 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=371 (M+H)+
Preparation 43
To a solution of ethyl 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoate (2.19 g) in the mixture of ethanol (22 ml) and tetrahydrofuran (22 ml) was added 2N NaOH aq. and refluxed for 5 hours. The reaction mixture was adjusted to pH 1-1.5 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (1.99 g).
IR (KBr): 1664.3, 1600.6, 1511.9, 1230.4 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.88 (3H, t, J=6.5 Hz), 1.2-1.5 (6H, m), 1.55-1.8 (2H, m), 3.0-3.6 (8H, m), 3.88 (2H, t, J=6.4 Hz) 6.83 (2H, d, J=9.2 Hz), 6.94 (2H, d, J=9.2 Hz), 7.01 (2H, d, J=8.9 Hz), 7.78 (2H, d, J=8.9 Hz).
The following compounds [Preparations 44 to 60] were obtained according to a similar manner to that of Preparation 43.
Preparation 44
4-[4-(trans-4-Cyclohexylcyclohexyl)piperazin-1-yl]benzoic acid hydrochloride
IR (KBr): 2919.7, 2852.2, 1695.1, 1606.4, 1234.2 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.8-2.0 (20H, m), 2.12 (1H, m), 2.9-3.6 (8H, m), 7.03 (2H, d, J=9.0 Hz), 7.81 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=371 (M+H)+
Preparation 45
4-[4-(cis-4-Cyclohexylcyclohexyl)piperazin-1-yl]benzoic acid hydrochloride
IR (KBr): 1693.2, 1604.5, 1232.3, 1186.0 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.8-2.0 (21H, m), 3.2-3.3 (8H, m), 7.03 (2H, d, J=9.0 Hz), 7.80 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=371 (M+H)+
Preparation 46
4-[4-(4-Cyclohexylphenyl)piperazin-1-yl]methylbenzoic acid hydrochloride
IR (KBr): 2925.5, 1704.8, 1251.6 cmxe2x88x921 
Preparation 47
4-[4-(4-Cyclohexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride
Preparation 48
4-[4-(4-Hexyloxyphenyl)piperidin-1-yl]benzoic acid
IR (KBr): 1670.1, 1602.6, 1513.8, 1394.3, 1216.9 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.5 Hz), 1.2-1.5 (6H, m), 1.5-1.9 (6H, m), 2.55-3.0 (3H, m), 3.95 (2H, t, J=6.5 Hz), 3.9-4.0 (2H, m), 6.84 (2H, d, J=8.7 Hz), 6.92 (2H, d, J=8.9 Hz), 7.15 (2H, d, J=8.7 Hz), 7.73 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=382 (M+H)+
Preparation 49
4-[4-(4-Hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl]benzoic acid
IR (KBr): 1668.1, 1602.6, 1513.8, 1230.4 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.88 (3H, m), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 2.5-2.7 (2H, m), 3.5-3.7 (2H, m), 3.8-4.1 (4H, m), 6.18 (1H, m), 6.90 (2H, d, J=8.8 Hz), 6.97 (2H, d, J=8.0 Hz), 7.40(2H, d, J=8.8 Hz), 7.78 (2H, d, J=8.0 Hz)
APCI-MASS: m/z=380 (M+H)+
Preparation 50
4-(4-n-Pentyloxyphenylethynyl)benzoic acid
IR (KBr): 2958, 2931, 1685, 1598, 1513, 1425, 1286, 1247 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.90 (3H, t, J=7.0 Hz), 1.3-1.5 (4H, m), 1.7-1.9 (2H, m), 4.01 (2H, t, J=6.5 Hz), 6.99 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.62 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 13.1 (1H, br s)
APCI-MASS: m/z=309 (M+H)+
Preparation 51
4-[5-[2-(4-n-Hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2935, 1679, 1513, 1241 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.5 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 3.03 (2H, t, J=7.5 Hz), 3.44 (2H, t, J=7.5 Hz), 3.91 (2H, t, J=6.5 Hz), 6.84 (2H, d, J=8.6 Hz), 7.18 (2H, d, J=8.6 Hz), 8.03 (2H, d, J=8.9 Hz), 8.08 (2H, d, J=8.9 Hz)
APCI-MASS: m/z=411 (M+H)+
Preparation 52
4-[5-(4-n-Pentylphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2954, 2923, 2854, 1685, 1604, 1429, 1288 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.6 Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, in), 2.67 (2H, t, J=7.6 Hz), 7.42 (2H, d, J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 8.11 (4H, s)
APCI-MASS: m/z=353 (M+H)+
Preparation 53
4-[5-(4-n-Hexylphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2954, 2921, 2852, 1685, 1429, 1290 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.93 (3H, t, J=6.7 Hz), 1.2-1.8 (8H, m), 2.73 (2H, t, J=7.7 Hz), 7.48 (2H, d, J=8.2 Hz), 8.01 (2H, d, J=8.1 Hz), 8.19 (4H, s)
APCI-MASS: m/z=367 (M+H)+
Preparation 54
4-[5-(4-n-Heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2923, 2856, 1689, 1604, 1430, 1292, 1250 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.88 (3H, t, J=6.5 Hz), 1.2-1.5 (8H, m), 1.6-1.8 (2H, m), 4.07 (2H, t, J=6.5 Hz), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.12 (4H, s)
APCI-MASS: m/z=397 (M+H)+
Preraration 55
4-[5-(4-n-Butoxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2958, 2869, 1687, 1604, 1432, 1294, 1251, 1174 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.95 (3H, t, J=7.3 Hz), 1.4-1.6 (2H, m), 1.7-1.9 (2H, m), 4.08 (2H, t, J=7.4 Hz), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.12 (4H, s)
APCI-MASS: m/z=355 (M+H)+
Preparation 56
4-[5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 1687, 1604, 1517, 1430, 1292, 1253, 1178 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 3.86 (3H, s), 7.14 (2H, d, J=8.9 Hz), 7.98 (2H, d, J=8.9 Hz), 8.12 (4H, s), 13.26 (1H, br s)
APCI-MASS: m/z=313 (M+H)+
Preparation 57
4-[5-[4-(3-Phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid
IR (KBr): 2948, 1689, 1602, 1411, 1292, 1243, 1174 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.22 (2H, tt, J=6.2 and 6.2 Hz), 4.15 (2H, t, J=6.2 Hz), 4.26 (2H, t, J=6.2 Hz), 6.9-7.0 (3H, m), 7.17 (2H, d, J=8.9 Hz), 7.2-7.4 (2H, m), 7.98 (2H, d, J=8.9 Hz), 8.12 (4H, s)
APCI-MASS: m/z=433 (M+H)+
Preparation 58
4-[5-(1-n-Octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]-benzoic acid hydrochloride
IR (KBr): 2933, 2871, 1714, 1438, 1278, 1110 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=0.9 Hz), 1.2-1.5 (10H, m), 1.6-2.4 (4H, m), 3.0-3.2 (2H, m), 3.3-3.4 (1H, m), 3.4-4.0 (4H, m), 8.10 (4H, s), 11.67 (1H, s)
APCI-MASS: m/z=402 (M+H)+
Preparation 59
4-[5-(4-n-Pentyloxyphenyl)thiophen-2-yl]benzoic acid
IR (KBr): 2956, 2935, 2867, 1685, 1604, 1288, 1251, 1182 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.90 (3H, t, J=6.9 Hz), 1.3-1.5 (4H, m), 1.6-1.8 (2H, m), 4.01 (2H, t, J=6.5 Hz), 6.98 (2H, d, J=8.8 Hz), 7.41 (1H, d, J=3.5 Hz), 7.5-7.7 (3H, m), 7.78 (2H, d, J=8.5 Hz), 7.95 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=367 (M+H)+
Preparation 60
4-[5-(4-n-Pentyloxyphenyl)furan-2-yl]benzoic acid
IR (KBr): 2958, 2935, 1681, 1608, 1538, 1294, 1253 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.91 (3H, t, J=6.9 Hz), 1.3-1.5 (4H, m), 1.6-1.8 (2H, m), 4.01 (2H, t, J=6.4 Hz), 6.96 (1H, d, J=3.5 Hz), 7.02 (2H, d, J=8.8 Hz), 7.19 (1H, d, J=3.5 Hz), 7.76 (2H, d, J=8.8 Hz), 7.85 (2H, d, J=8.5 Hz), 7.98 (2H, d, J=8.5 Hz)
APCI-MASS: m/z=351 (M+H)+
Preparation 61
To a suspension of 3-(4-n-hexyloxyphenyl)propiono-hydrazide (0.92 g) in tetrahydrofuran (25 ml) and pyridine (0.84 ml) was added a solution of 4-methoxycarbonylbenzoyl chloride (0.73 g) in tetrahydrofuran (10 ml) dropwise at 5xc2x0 C. The reaction mixture was stirred for 1 hour and poured into ice-water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.43 g).
IR (KBr): 3234, 2929, 1724, 1689, 1646, 1515, 1282, 1108 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.4 Hz), 1.3-1.5 (6H, m), 1.6-1.8 (2H, m), 2.4-2.5 (2H, m), 2.81 (2H, d, J=7.7 Hz), 3.89 (3H, s), 3.91 (2H, t, J=6.5 Hz), 6.83 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.6 Hz), 7.98 (2H, d, J=8.5 Hz), 8.07 (2H, d, J=8.5 Hz), 9.97 (1H, s), 10.51 (1H, s)
APCI-MASS: m/z=427 (M+H)+
The following compounds [Preparations 62 to 68] were obtained according to a similar manner to that of Preparation 61.
Preparation 62
1-(4-Methoxycarbonylbenzoyl)-2-(4-n-pentylbenzoyl)-hydrazine
IR (KBr): 2958, 2929, 1724, 1685, 1646, 1282 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.86 (3H, t, J=6.7 Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m), 2.65 (2H, t, J=6.8 Hz), 3.90 (3H, s), 7.34 (2H, d, J=8.1 Hz), 7.84 (2H, d, J=8.1 Hz), 8.05 (2H, d, J=3.4 Hz), 8.07 (2H, d, J=3.4 Hz), 10.50 (1H, s), 10.69 (1H, s)
APCI-MASS: m/z=369 (M+H)+
Preparation 63
1-[N-(tert-Butoxycarbonyl)piperidin-4-yl)carbonyl]-2-(4-methoxycarbonylbenzoyl)hydrazine
IR (KBr): 3291, 2940, 1727, 1664, 1540, 1436, 1278 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.41 (9H, s), 1.4-1.9 (4H, m), 2.3-2.5 (1H, m), 2.79 (2H, t, J=11.5 Hz), 3.89 (3H, s), 3.96 (2H, d, J=13.5 Hz), 7.97 (2H, d, J=8.6 Hz), 8.06 (2H, d, J=8.6 Hz), 9.96 (1H, s), 10.50 (1H, s)
APCI-MASS: m/z=306 (Mxe2x88x92Boc)+
Preparation 64
1-(4-Methoxycarbonylbenzoyl)-2-[4-(3-phenoxypropyloxy)-benzoyl]hydrazine
IR (KBr): 3228, 2950, 2883, 1722, 1685, 1645, 1604, 1465, 1280, 1247 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 2.21 (2H, tt, J=6.2 and 6.2 Hz), 3.91 (3H, s), 4.15 (2H, t, J=6.2 Hz), 4.23 (2H, t, J=6.2 Hz), 6.9-7.1 (3H, m), 7.08 (2H, d, J=8.8 Hz), 7.29 (2H, dd, J=8.8 and 7.2 Hz), 7.91 (2H, d, J=8.8 Hz), 8.03 (2H, d, J=8.6 Hz), 8.10 (2H, d, J=8.6 Hz), 10.42 (1H, S), 10.63 (1H, s)
APCI-MASS: m/z=449 (M+H)+
Preparation 65
1-(4-Methoxybenzoyl)-2-(4-methoxycarbonylbenzoyl)-hydrazine
IR (KBr): 3267, 3068, 1722, 1679, 1643, 1610, 1558, 1506, 1284, 1257 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 3.84 (3H, s), 3.90 (3H, s), 7.06 (2H, d, J=8.9 Hz), 7.92 (2H, d, J=8.9 Hz), 8.03 (2H, d, J=8.7 Hz), 8.10 (2H, d, J=8.7 Hz), 10.42 (1H, s), 10.63 (1H, s)
APCI-MASS: m/z=329 (M+H)+
Preparation 66
1-(4-n-Butoxybenzoyl)-2-(4-methoxycarbonylbenzoyl)-hydrazine
IR (KBr): 3305, 2956, 1724, 1683, 1643, 1610, 1284, 1251, 1184, 1108 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.94 (3H, t, J=7.3 Hz), 1.4-1.6 (2H, m), 1.6-1.8 (2H, m), 3.90 (3H, s), 4.06 (2H, t, J=6.4 Hz), 7.05 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8 Hz), 8.03 (2H, d, J=8.6 Hz), 8.10 (2H, d, J=8.6 Hz), 10.42 (1H, s), 10.64 (1H, s)
APCI-MASS: m/z=371 (M+H)+
Preparation 67
1-(4-n-Heptyloxybenzoyl)-2-(4-methoxycarbonylbenzoyl)-hydrazine
IR (KBr): 3237, 2929, 2858, 1726, 1683, 1643, 1610, 1284, 1253 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.87 (3H, t, J=6.5 Hz), 1.2-1.5 (8H, m), 1.6-1.8 (2H, m), 3.90 (3H, s), 4.04 (2H, d, J=6.4 Hz), 7.04 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8 Hz), 8.03 (2H, d, J=8.6 Hz), 8.10 (2H, d, J=8.6 Hz), 10.42 (1H, s), 10.64 (1H, s)
APCI-MASS: m/z=413 (M+H)+
Preparation 68
1-(4-n-Hexylbenzoyl)-2-(4-methoxycarbonylbenzoyl)-hydrazine
IR (KBr): 3330, 2958, 2925, 2854, 1726, 1685, 1647, 1282, 1108 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.86 (3H, t, J=6.6 Hz), 1.2-1.4 (6H, m), 1.5-1.7 (2H, m), 2.65 (2H, t, J=7.5 Hz), 3.90 (3H, s), 7.34 (2H, d, J=8.2 Hz), 7.84 (2H, d, J=8.2 Hz), 8.0-8.2 (4H, m), 10.50 (1H, s), 10.68 (1H, s)
APCI-MASS: m/z=383 (M+H)+
Preparation 69
A suspension of 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.0 g) and diphosphorus pentasulfide (730 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour at 60xc2x0 C. To a reaction mixture was added water and the mixture was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-[2-(4-n-hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoate (883 mg).
IR (KBr): 2927, 1724, 1513, 1280, 1108 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m), 3.11 (2H, t, J=7.6 Hz), 3.46 (2H, t, J=7.6 Hz), 3.93 (2H, t, J=6.5 Hz), 3.95 (3H, s), 6.84 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.6 Hz), 7.98 (2H, d, J=8.4 Hz), 8.12 (2H, d, J=8.4 Hz)
APCI-MASS: m/z=425 (M+H)+
The following compounds [Preparations 70 to 76] were obtained according to a similar manner to that of Preparation 69.
Preparation 70
Methyl 4-[5-(4-n-pentylphenyl)-1,3,4-thiadiazol-2-yl]-benzoate
IR (KBr): 2956, 2929, 2856, 1722, 1434, 1280, 1110 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.7 Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m), 2.68 (2H, t, J=7.7 Hz), 3.96 (3H, s), 7.31 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz), 8.07 (2H, d, J=8.0 Hz), 8.16 (2H, d, J=8.0 Hz)
APCI-MASS: m/z=367 (M+H)+
Preparation 71
Methyl 4-[5-[N-(tert-butoxycarbonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-yl]benzoate
IR (KBr): 2975, 1716, 1691, 1403, 1276, 1238, 1174, 1112 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.49 (9H, s), 1.7-1.9 (2H, m), 2.1-2.2 (2H, m), 2.8-3.0 (2H, m), 3.3-3.5 (1H, m), 3.96 (3H, s), 4.22 (2H, d, J=13.3 Hz), 8.01 (2H, d, J=8.8 Hz), 8.14 (2H, d, J=8.8 Hz)
APCI-MASS: m/z=304 (Mxe2x88x92Boc)+
Preparation 72
Methyl 4-[5-[4-(3-phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoate
IR (KBr): 2954, 1727, 1602, 1436, 1284, 1251, 1182 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.30 (2H, tt, J=6.1 and 6.1 Hz), 3.96 (3H, s), 4.18 (2H, t, J=6.1 Hz), 4.25 (2H, t, J=6.1 Hz), 6.9-7.0 (3H, m), 7.02 (2H, d, J=8.8 Hz), 7.2-7.4 (2H, m), 7.95 (2H, d, J=8.5 Hz), 8.06 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=447 (M+H)+
Preparation 73
Methyl 4-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoate
IR (KBr): 2952, 1710, 1606, 1517, 1432, 1278, 1251, 1180, 1110 cmxe2x88x921 
NMR (CDCl3, xcex4): 3.88 (3H, s), 3.95 (3H, s), 6.98 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.07 (2H, d, J=8.6 Hz), 8.13 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=327 (M+H)+
Preparation 74
Methyl 4-[5-(4-n-butoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoate
IR (KBr): 2962, 2942, 2873, 1718, 1606, 1436, 1280, 1251, 1180 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.00 (3H, t, J=7.3 Hz), 1.4-1.6 (2H, m), 1.7-1.9 (2H, m), 3.95 (3H, s), 4.03 (2H, t, J=6.5 Hz), 6.99 (2H, d, J=8.9 Hz), 7.94 (2H, d, J=8.9 Hz), 8.06 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=369 (M+H)+
Preparation 75
Methyl 4-[5-(4-n-heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate
IR (KBr): 2933, 2861, 1718, 1515, 1434, 1278, 1106 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.3-1.6 (8H, m), 1.8-2.0 (2H, m), 3.95 (3H, s), 4.03 (2H, t, J=6.5 Hz), 6.99 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.06 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=411 (M+H)+
Preparation 76
Methyl 4-[5-(4-n-hexylphenyl)-1,3,4-thiadiazol-2-yl]-benzoate
IR (KBr): 2925, 2854, 1720, 1432, 1280, 1110 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.89 (3H, t, J=6.6 Hz), 1.3-1.7 (6H, m), 2.67 (2H, t, J=7.7 Hz), 3.96 (3H, s), 7.31 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz), 8.07 (2H, d, J=8.6 Hz), 8.16 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=381 (M+H)+
Preparation 77
To a solution of 1-hydroxybenzotriazole (5.35 g) and 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (15 g) in the mixture of triethylamine (9.64 ml) and dichloromethane (450 ml) was added 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (12.6 g) and stirred for 4 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoyloxy]benzotriazole (16.78 g).
IR (KBr): 1783.8, 1600.6, 1511.9, 1232.3, 1184.1 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m), 3.1-3.3 (4H, m), 3.5-3.7 (4H, m), 3.93 (2H, t, J=6.5 Hz), 6.87 (2H, d, J=9.2 Hz), 6.95 (2H, d, J=9.2 Hz), 7.00 (2H, d, J=9.2 Hz), 7.35-7.6 (3H, m), 8.09 (1H, d, J=8.2 Hz), 8.15 (2H, d, J=9.2 Hz)
The following compounds [Preparations 78 to 97] were obtained according to a similar manner to that of Preparation 77.
Preparation 78
1-[4-[4-(trans-4-Cyclohexylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole
IR (KBr): 2925.5, 1764.5, 1600.6, 1234.2 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.8-1.4 (12H, m), 1.5-2.1 (8H, m), 2.27 (1H, m), 2.6-2.8 (4H, m), 3.4-3.6 (4H, m), 6.93 (2H, d, J=9.1 Hz), 7.3-7.6 (3H, m), 8.08 (1H, d, J=8.1 Hz), 8.11 (2H, d, J=9.1 Hz)
APCI-MASS: m/z=488 (M+H)+
Preparation 79
1-[4-[4-(cis-4-Cyclohexylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole
IR (KBr): 1762.6, 1600.6, 1232.3, 1186.0 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.8-2.0 (20H, m), 2.26 (1H, m), 2.6-2.8 (4H, m), 3.4-3.6 (4H, m), 6.94 (2H, d, J=9.0 Hz), 7.35-7.6 (3H, m), 8.08 (1H, d, J=8.1 Hz), 8.11 (2H, d, J=9.0 Hz)
APCI-MASS: m/z=488 (M+H)+
Preparation 80
1-[4-[4-(4-Cyclohexyloxyphenyl)piperazin-1-yl]-benzoyloxy]benzotriazole
Preparation 81
1-[4-[4-(4-Morpholinophenyl)piperazin-1-yl]benzoyloxy]-benzotriazole
IR (KBr): 1780.0, 1600.6, 1513.8, 1232.3, 1184.1 cmxe2x88x921 
NMR (CDCl3, xcex4): 3.09 (4H, t, J=4.8 Hz), 3.26 (4H, t, J=5.1 Hz), 3.62 (4H, t, J=5.1 Hz), 3.87 (4H, t, J=4.8 Hz), 6.91 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=9.0 Hz), 7.35-7.6 (3H, m), 8.09 (1H, d, J=7.1 Hz), 8.15 (2H, d, J=9.1 Hz)
Preparation 82
1-[4-[4-(4-Hexyloxyphenyl)-4-hydroxypiperidin-1-yl]-benzoyloxy]benzotriazole
IR (KBr): 3513.7, 1733.7, 1598.7, 1186.0 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.5 Hz), 1.2-2.05 (11H, m), 2.05-2.3 (2H, m), 3.4-3.6 (2H, m), 3.8-4.0 (2H, m), 3.96 (2H, t, J=6.5 Hz), 6.90xe2x80x2(2H, d, J=8.8 Hz), 7.00 (2H, d, J=9.2 Hz), 7.3-7.6 (5H, m), 8.07 (1H, d, J=8.2 Hz), 8.12 (2H, d, J=9.2 Hz)
APCI-MASS: m/z=515 (M+H)+
Preparation 83
1-[4-[4-(4-Hexyloxyphenyl)piperidin-1-yl]benzoyloxy]-benzotriazole
IR (KBr): 2933.2, 1768.4, 1602.6, 1515.8, 1259.3, 1186.0 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.7-2.1 (6H, m), 2.65-2.9 (1H, m), 3.0-3.2 (2H, m), 3.94 (2H, t, J=6.5 Hz), 4.05-4.2 (2H, m), 6.86 (2H, d, J=8.7 Hz), 6.98 (2H d, J=9.1 Hz), 7.14 (2H, d, J=8.7 Hz), 7.35-7.6 (3H, m), 8.08 (1H, d, J=8.2 Hz), 8.12 (2H, d, J=9.1 Hz)
Preparation 84
1-[4-[4-(4-Pentyloxyphenyl)phenyl]benzoyloxy]-benzotriazole
Preparation 85
1-[4-[4-(3-Hexyloxyphenyl)piperazin-1-yl]benzoyloxy]-benzotriazole
IR (KBr): 1774.2, 1602.6, 1236.1, 1187.9 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.6 Hz), 1.2-1.6 (6H, m), 1.7-1.9 (2H, m), 3.3-3.5 (4H, m), 3.5-3.7 (4H, m), 3.96 (2H, t, J=6.5 Hz), 6.47 (1H, d, J=8.0 Hz), 6.51 (1H, s), 6.56 (1H, d, J=8.0 Hz), 6.98 (2H, d, J=9.0 Hz), 7.20 (1H, dd, J=8.0 Hz), 7.3-7.6 (3H, m), 8.08 (1H, d, J=8.2 Hz), 8.15 (2H, d, J=9.0 Hz)
Preparation 86
1-[4-[4-(4-Hexyloxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl]benzoyloxy]benzotriazole
IR (KBr): 1766.5, 1600.6, 1513.8, 1232.3, 1182.2 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.5 Hz), 1.2-1.6 (6H, m), 1.6-1.9 (2H, m), 2.6-2.8 (2H, m), 3.75 (2H, t, J=5.7 Hz), 3.97 (2H, t, J=6.5 Hz), 4.05-4.2 (2H, m), 6.0-6.15 (1H, m), 6.89 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=9.1 Hz), 7.35 (2H, d, J=8.8 Hz), 7.3-7.6 (3H, m), 8.08 (1H, d, J=8.2 Hz), 8.14 (2H, d, J=9.1 Hz)
Preparation 87
1-[4-[4-(1-Cyclohexylpiperidin-4-yl)piperidin-1-yl]-benzoyloxy]benzotriazole
IR (KBr): 1766.5, 1606, 1240, 1186.0, 918.0 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.0-2.5 (23H, m), 2.8-3.2 (4H, m), 3.9-4.1 (2H, m), 6.92 (2H, d, J=9.1 Hz), 7.3-7.6 (3H, m), 8.0-8.2 (3H, m)
APCI-MASS: m/z=488 (M+H)+
Preparation 88
1-[4-[5-[2-(4-n-Hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole
IR (KBr): 2942, 2865, 1785, 1513, 1240, 995 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.6 Hz), 1.2-1.5 (6H, m), 1.7-1.9 (2H, m), 3.14 (2H, t, J=7.6 Hz), 3.50 (2H, t, J=7.6 Hz), 3.94 (2H, t, J=6.5 Hz), 6.85 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.6 Hz), 7.4-7.6 (3H, m), 8.1-8.2 (1H, m), 8.16 (2H, d, J=8.6 Hz), 8.38 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=528 (M+H)+
Preparation 89
1-[4-[5-(4-n-Pentylphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole
IR (KBr): 2956, 2929, 2865, 1776, 1608, 1434, 1402, 1232 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.6 Hz), 1.2-1.4 (4H, m), 1.5-1.7 (2H, m), 2.70 (2H, t, J=7.7 Hz), 7.34 (2H, d, J=8.3 Hz), 7.4-7.6 (3H, m), 7.96 (2H, d, J=8.3 Hz), 8.12 (1H, d, J=9.1 Hz), 8.26 (2H, d, J=8.7 Hz), 8.41 (2H, d, J=8.7 Hz)
APCI-MASS: m/z=470 (M+H)+
Preparation 90
1-[4-[5-(4-n-Hexylphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole
IR (KBr): 2956, 2925, 2856, 1770, 1606, 1434, 1232, 1029 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.90 (3H, t, J=6.6 Hz), 1.2-1.5 (6H, m), 1.6-1.8 (2H, m), 2.69 (2H, t, J=7.7 Hz), 7.33 (2H, d, J=8.3 Hz), 7.4-7.6 (3H, m), 7.95 (2H, d, J=8.3 Hz), 8.12 (1H, d, J=8.1 Hz), 8.25 (2H, d, J=8.7 Hz), 8.40 (2H, d, J=8.7 Hz)
APCI-MASS: m/z=484 (M+H)+
Preparation 91
1-[4-[5-(4-n-Heptyloxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole
IR (KBr): 2925, 2856, 1770, 1602, 1440, 1263, 1222, 1029 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.91 (3H, t, J=6.5 Hz), 1.2-1.6 (8H, m), 1.7-1.9 (2H, m), 4.04 (2H, t, J=6.5 Hz), 7.01 (2H, d, J=8.8 Hz), 7.4-7.7 (3H, m), 7.97 (2H, d, J=8.8 Hz), 8.12 (1H, d, J=8.2 Hz), 8.24 (2H, d, J=8.6 Hz), 8.40 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=514 (M+H)+
Preparation 92
1-[4-[5-(4-n-Butoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole
IR (KBr): 2956, 2873, 1774, 1602, 1442, 1251, 1180 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.00 (3H, t, J=7.2 Hz), 1.5-1.7 (2H, m), 1.7-1.9 (2H, m), 4.06 (2H, t, J=6.7 Hz), 7.02 (2H, d, J=8.7 Hz), 7.4-7.6 (3H, m), 7.98 (2H, d, J=8.7 Hz), 8.13 (1H, d, J=8.0 Hz), 8.25 (2H, d, J=8.2 Hz), 8.41 (2H, d, J=8.2 Hz)
APCI-MASS: m/z=472 (M+H)+
Preparation 93
1-[4-[5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-yl]-benzoyloxy]benzotriazole
NMR (CDCl3, xcex4): 3.91 (3H, s), 7.04 (2H, d, J=8.9 Hz), 7.2-7.5 (3H, m), 8.00 (2H, d, J=8.9 Hz), 8.13 (1H, d, J=8.1 Hz), 8.25 (2H, d, J=8.7 Hz), 8.42 (2H, d, J=8.7 Hz)
Preparation 94
1-[4-[5-[4-(3-Phenoxypropyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole
IR (KBr): 2927, 1778, 1603, 1438, 1240, 1178 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.31 (2H, tt, J=6.0 and 6.0 Hz), 4.19 (2H, t, J=6.0 Hz), 4.27 (2H, t, J=6.0 Hz), 6.93 (2H, d, J=8.8 Hz), 7.0-7.2 (3H, m), 7.2-7.6 (5H, m), 7.98 (2H, d, J=8.8 Hz), 8.13 (1H, d, J=8.3 Hz), 8.25 (2H, d, J=8.3 Hz), 8.41 (2H, d, J=8.3 Hz)
APCI-MASS: m/z=550 (M+H)+
Preparation 95
1-[4-[5-(1-n-Octylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl]benzoyloxy]benzotriazole
IR (KBr): 3421, 2925, 2856, 1697, 1452, 1380, 1259, 1099 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.89 (3H, t, J=6.8 Hz), 1.2-1.7 (12H, m), 1.9-2.5 (10H, m), 3.0-3.2 (2H, m), 3.2-3.4 (1H, m), 7.4-7.6 (3H, m), 8.12 (1H, d, J=8.1 Hz), 8.20 (2H, d, J=8.6 Hz), 8.39 (2H, d, J=8.6 Hz)
APCI-MASS: m/z=519 (M+H)+
Preparation 96
1-[4-[5-(4-n-Pentyloxyphenyl)thiophen-2-yl]benzoyloxy]-benzotriazole
IR (KBr): 2865, 1772, 1691, 1600, 1540, 1513, 1454, 1251, 1180 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.95 (3H, t, J=7.2 Hz), 1.3-1.6 (4H, m), 1.7-2.0 (2H, m), 4.00 (2H, t, J=6.4 Hz), 6.94 (2H, d, J=8.4 Hz), 7.25 (1H, d, J=3.5 Hz), 7.4-7.7 (6H, m), 7.81 (2H, d, J=8.1 Hz), 8.11 (1H, d, J=8.4 Hz), 8.27 (2H, d, J=8.1 Hz)
APCI-MASS: m/z=484 (M+H)+
Preparation 97
1-[4-[5-(4-n-Pentyloxyphenyl)furan-2-yl]benzoyloxy]-benzotriazole
IR (KBr): 2948, 2865, 1778, 1600, 1502, 1479, 1253 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.95 (3H, t, J=7.2 Hz), 1.3-1.6 (4H, m), 1.7-1.9 (2H, m), 4.01 (2H, t, J=6.5 Hz), 6.68 (1H, d, J=3.6 Hz), 6.9-7.1 (3H, m), 7.4-7.6 (3H, m), 7.71 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.7 Hz), 8.11 (1H, d, J=8.2 Hz), 8.28 (2H, d, J=8.7 Hz)
APCI-MASS: m/z=468 (M+H)+
Preparation 98
To a solution of 4-n-pentyloxybenzoic acid benzotriazole-1-yl ester (20 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (6.73 g) and stirred for 7 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g).
IR (KBr): 3419.2, 3151.1, 1691.3, 1259.3 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.90 (3H, t, J=7.0 Hz), 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 4.02 (2H, t, J=6.5 Hz), 6.98 (2H, d, J=8.8 Hz), 7.58 (2H, s), 9.28 (1H, s), 10.22 (1H, s)
APCI-MASS: m/z=282 (M+H)+
Preparation 99
To a slurry of 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g) in toluene (213.3 ml) at 40xc2x0 C., was added dropwise over 30 minutes, methanesulfonic acid (6.92 ml). The mixture was refluxed for 12 hours. After cooling to 10xc2x0 C, the resulting precipitate was filtered and dried. The precipitate was dissolved in water, the solution was adjusted to pH 9 with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 2-amino-5-(4-n-pentyloxyphenyl)-1,3,4-thiadiazole (4.314 g).
IR (KBr): 3261.0, 3174.3, 1608.3, 1255.4 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.94 (3H, t, J=7.0 Hz), 1.2-1.6 (4H, m), 1.6-1.9 (2H, m), 3.99 (2H, t, J=6.5 Hz), 5.53 (2H, s), 6.92 (2H, d, J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz)
APCI-MASS: m/z=264 (M+H)+
Preparation 100
To a suspension of 2-amino-5-(4-n-pentyloxyphenyl)-1,3,4-thiadiazole (4.314 g) in ethanol (43 ml) was added ethyl 4-bromoacetylbenzoate (4.21 g) and refluxed for 4 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was filtered and dried. To a suspension of the powder in xylene (40 ml) was added trifluoroacetic acid (10 ml) and refluxed for 3 hours. The reaction mixture was pulverized with diisopropyl ether. The precipitate was filtered and dried to give 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (5.3 g).
IR (KBr): 1710.6, 1610.3, 1272.8 cmxe2x88x921 
APCI-MASS: m/z=436 (M+H)+
Preparation 101
To a solution of 4-[2-(4-pentyloxyphenyl)imidazo-[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (5.2 g) in the mixture of methanol (104 ml) and tetrahydrofuran (52 ml) was added 2N NaOH aq. (47 ml) and refluxed for 36 hours. The reaction mixture was adjusted to pH 1-2 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[2-(4-pentyloxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.27 g).
IR (KBr): 1681.6, 1606.4, 1255.4, 1174.4 cmxe2x88x921 
APCI-MASS: m/z=408 (M+H)+
Preparation 102
To a solution of 1-hydroxybenzotriazole (1.67 g) and 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoic acid (4.2 g) in dichloromethane (170 ml) was added 1-ethyl-3-(31-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (2.95 g) and stirred for 6 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoyloxy]benzotriazole (2.456 g).
IR (KBr): 1772.3, 1604.5, 1251.6, 983.5 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.96 (3H, t, J=7.0 Hz), 1.2-1.6 (4H, m), 1.6-1.9 (2H, m), 4.05 (2H, t, J=6.5 Hz), 7.01 (2H, d, J=8.3 Hz), 7.4-7.6 (3H, m), 7.83 (2H, d, J=8.3 Hz), 8.07 (2H, d, J=8.0 Hz), 8.10 (1H, d, J=8.2 Hz), 8.21 (1H, s), 8.33 (2H, d, J=8.0 Hz)
APCI-MASS: m/z=525 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 98.
Preparation 103
1-[4-(4-Ethoxyphenyl)benzoyl]-3-thiosemicarbazide
IR (KBr): 3295.7, 3263.0, 1668.1, 1257.4 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.35 (3H, t, J=7.0 Hz), 4.08 (2H, q, J=7.0 Hz), 7.03 (2H, d, J=8.8 Hz), 7.68 (2H, d, J=8.8 Hz), 7.6-8.1 (6H, m), 9.35 (1H, s), 10.40 (1H, s)
APCI-MASS: m/z=316 (M+H)+
The following compounds [Preparations 104 and 105] were obtained according to a similar manner to that of Preparation 99.
Preparation 104
2-Amino-5-[4-(4-ethoxyphenyl)phenyl]-1,3,4-thiadiazole
IR (KBr): 3432.7, 1602.6, 1500.3, 825.4 cmxe2x88x921 
Preparation 105
2-Amino-5-(4-phenylphenyl)-1,3,4-thiadiazole
IR (KBr): 3278.4, 3085.5, 1643.1, 1513.8 cmxe2x88x921 
APCI-MASS: m/z=254 (M+H)+
The following compounds [Preparations 106 and 107] were obtained according to a similar manner to that of Preparation 100.
Preparation 106
4-[2-[4-(4-Ethoxyphenyl)phenyl]imidazo[2,1-b][1,3,4]-thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt
IR (KBr): 1708.6, 1604.5, 1274.7, 1105.0, 819.6, 729.0 cmxe2x88x921 
APCI-MASS: m/z=470 (M+H)+
Preparation 107
4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt
IR (KBr): 1710.6, 1606.4, 1278.6, 1106.9 cmxe2x88x921 
APCI-MASS: m/z=426 (M+H)+
The following compounds [Preparations 108 to 110] were obtained according to a similar manner to that of Preparation 101.
Preparation 108
4-[2-[4-(4-Ethoxyphenyl)phenyl]imidazo[2,1-b][1,3,4]-thiadiazol-6-yl]benzoic acid
IR (KBr): 1683.6, 1604.5, 1278.6, 1253.5, 821.5, 727.0 cmxe2x88x921 
Preparation 109
4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid
IR (KBr): 1706.7, 1608.3, 1276.6, 1251.6 cmxe2x88x921 
APCI-MASS: m/z=398 (M+H)+
Preparation 110
4-[4-(4-n-Pentylcyclohexyl)piperazin-1-yl]benzoic acid monohydrochloride
IR (KBr): 2923.6, 2854.1, 1693.2, 1610.3 cmxe2x88x921 
APCI-MASS: m/z=359 (M+H)+
The following compounds [Preparations 111 and 112] were obtained according to a similar manner to that of Preparation 102.
Preparation 111
1-[4-[2-[4-(4-Ethoxyphenyl)phenyl]imidazo[2,1-b][1,3,4]-thiadiazol-6-yl]benzoyloxy]benzotriazole
IR (KBr): 1778.0, 1714.4, 1602.6, 1276.6, 1255.4, 821.5, 779.1 cmxe2x88x921 
APCI-MASS: m/z=559 (M+H)+
Preparation 112
1-[4-[2-(4-Phenylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoyloxy]benzotriazole
IR (KBr): 1778.0, 1714.4, 1606.4, 1278.6, 1251.6, 821.5, 723.2 cmxe2x88x921 
APCI-MASS: m/z=515 (M+H)+
Preparation 113
To a solution of 4-phenylbenzoic acid (10.0 g), 1-hydroxybenzotriazole (7.5 g) and thiosemicarbazide (5.1 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl) carbodiimide hydrochloride (14.45 g) and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried under reduced pressure to give 1-(4-phenylbenzoyl)-3-thiosemicarbazide (10.274 g).
IR (KBr): 3369.0, 3185.8, 1656.6, 1610.3, 1261.2, 744.4 cmxe2x88x921 
APCI-MASS: m/z=272 (M+H)+
The following compounds [Preparations 114 and 115] were obtained according to a similar manner to that of Preparation 77.
Preparation 114
1-[4-[4-(4-n-Pentylcyclohexyl)piperazin-1-yl]-benzoyloxy]benzotriazole
IR (KBr): 2919.7, 2848.3, 1778.0, 1600.6, 1232.3 cmxe2x88x921 
NMR (CDCl3, xcex4): 0.89 (3H, t, J=6.6 Hz), 0.8-1.1 (2H, m), 1.1-2.0 (15H, m), 2.6-2.8 (4H, m), 3.4-3.6 (4H, m), 6.93 (2H, d, J=9.2 Hz), 7.4-7.6 (3H, m), 8.0-8.2 (3H, m)
APCI-MASS: m/z=476 (M+H)+
Preparation 115
1-[4-[2-[4-(4-Cyclohexylphenyl)piperazin-1-yl]ethyl]-benzoyloxy]benzotriazole
IR (KBr): 2923.6, 1799.3, 1781.9, 1608.3, 1232.3, 979.7 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.1-1.6 (6H, m), 1.6-2.1 (4H, m), 2.43 (1H, m), 2.6-2.8 (6H, m), 2.9-3.1 (2H, m), 3.2-3.4 (4H, m), 6.88 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.3 Hz), 7.4-7.7 (3H, m), 8.11 (1H, dd, J=1.4 and 7.7 Hz), 8.21 (2H, d, J=8.3 Hz)
APCI-MASS: m/z=510 (M+H)+
Preparation 116
To a suspension of 1-(4-cyclohexylphenyl)piperazine dihydrobromide (2.5 g) and potassium bicarbonate (2.125 g) in N,N-dimethylformamide (6 ml) was added methyl 4-(2-chloroethylphenyl) benzoate (1.22 g) and stirred for 24 hours at 120xc2x0 C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-[2-[4-(4-cyclohexylphenyl)-piperazin-1-yl]ethyl]benzoate (1.247 g).
IR (KBr): 2927.4, 2852.2 1724.0, 1652.7, 1278.6 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.2-1.5 (5H, m), 1.7-2.0 (5H, m), 2.42 (1H, m), 2.6-2.8 (6H, m), 2.8-3.0 (2H, m), 3.1-3.3 (4H, m), 3.91 (3H, s), 6.87 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz), 7.29 (2H, d, J=8.3 Hz), 7.96 (2H, d, J=8.3 Hz)
APCI-MASS: m/z=407 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 43.
Preparation 117
4-[2-[4-(4-Cyclohexylphenyl)piperazin-1-yl]ethyl]benzoic acid
IR (KBr): 3673.7, 3648.7, 1710.6, 1515.8, 1243.9, 1228.4 cmxe2x88x921 
APCI-MASS: m/z=393 (M+H)+
Preparation 118
To a solution of 4-(4xe2x80x2-hydroxyphenyl)benzoic acid (15.00 g) in dimethylformamide (150 ml) were added successively n-propyl bromide (14.63 ml) and potassium carbonate (24.19 g). The mixture was stirred at 60xc2x0 C. for 24 hours, during this period additional n-propyl bromide (1.27 ml) and potassium carbonate (1.94 g) were added into the mixture. After cooling to room temperature, the reaction mixture was poured into water (600 ml) and then the mixture was stirred for 30 minutes at room temperature. The resulting precipitate was filtered, washed with water, and dried to give the objective compound, propyl 4-(4xe2x80x2-propoxyphenyl)benzoate (20.48 g), as a white solid.
IR (KBr): 2966, 1711, 1605 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.06 (6H, m), 1.83 (4H, m), 3.97 (2H, t, J=6.6 Hz), 4.30 (2H, t, J=6.6 Hz), 6.98 (2H, m), 7.59 (4H, m), 8.08 (2H, m)
APCI-MASS: m/z=299 (M+H)+
Preparation 119
To a mixture of propyl 4-(4xe2x80x2-propoxyphenyl)benzoate (20.00 g) in a mixture of ethanol (100 ml) and tetrahydrofuran (40 ml) was added hydrazine monohydrate (32.5 ml). The mixture was refluxed for 2 hours, during this period additional hydrazine monohydrate (32.5 ml) was added into the mixture. After cooling to room temperature, the reaction mixture was poured into water (1800 ml) and then the mixture was stirred for 30 minutes at room temperature. The resulting precipitate was filtered, washed with water, and dried to give the objective compound, 4-(4xe2x80x2-propoxyphenyl)-benzoyl hydrazine (17.63 g), as a white solid.
IR (KBr): 3338, 3277, 3194, 2966, 2929, 1612 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 0.99 (3H, t, J=7.4 Hz), 1.75 (2H, m), 3.98 (2H, t, J=6.5 Hz), 4.50 (2H, s), 7.03 (2H, d, J=8.8 Hz), 7.68 (4H, m), 7.89 (2H, d, J=8.4 Hz), 9.79 (1H, s)
APCI-MASS: m/z=271 (M+H)+
The Starting Compound in the following Examples 1 to 30 and The Object Compounds (1) to (30) in the following Examples 1 to 30 are illustrated by chemical formulae as below.
The Starting Compound (the same in Examples 1 to 30) 
The object Compounds (1) to (30) 
In the following Examples, The Object Compound (X) [e.g. The Object Compound (1)] means the object compound of Example (X) [e.g. Example (1)].